Therapeutic composition



United States Patent THERAPEUTIC COMPOSITION Charles H. Tilford, Cincinnati, Ohio, Frederick J. McCarty, Ann Arbor, Mich., and Marcus G. Van Campen, Jr., Berkeley, Calif., assignors to The Wm. S. Merrell Company No Drawing. pplication January 6, 1958 Serial No. 707,445

6 Claims. (Cl. 260-244) This invention relates to new chemical compounds which are useful as stimulants or depressants for the central nervous system.

The new compounds include (a) saturated, substituted oxazolopyridines of the formula (b) saturated substituted 3-oXa-5-azabicyclo [3.1.3] nonanes of the formula and (cl saturated substituted 3-oxa-5-azabicyclo [3.2.2] nonanes of the formula R s \o N 04.

in which s signifies saturation of the rings, n is an integer from 1 to 4 inclusive, R represents a hydrogen atom or a methyl or ethyl radical, and R and R' represent substituents selected from the group consisting of the phenyl, phenyl lower alkyl, lower alkylphenyl, lower alkoxyphenyl, halophenyl and thienyl radicals, and in which R" and R when takenftogether with the carbon atom to which they are attached represent a 9(10) -anthranylidene radical.

More specifically, the radicals represented by R" and R' include lower alkylphenyl and lower alkoxyphenyl radicals in which the one or more alkyl or alkoxy side chains each contain from 1 to 4 or more carbon atoms,

phenyl lower alkyl radicals having a phenyl nucleus attached to an alkyl chain of 1 to 4 or more carbon atoms, e.g., benzyl, phenetyl and the like, and halophenyl radicals in which the phenyl nucleus is substituted with one or more fluorine, chlorine, bromine or iodine atoms in the ortho, meta or para positions.

The new compounds are basic, and are ordinarily used in the form of the acid addition salts such as the hydrochloride, hydrobromide, sulfate, succinate, phosphate, glycolate, acetate, tartrate, levulinate, maleate, and the like. The hydrochloride salts, however, have a tendency to hydrolyze to the corresponding piperidinemethanols and, therefore, the maleate salts, which do not hydrolyze, are preferred. The new compounds can be administered orally in tablet or other suitable form or parenterally, e.g., intravenously.

ice

The new compounds can be used orally and parenterally in doses ranging between about 25 mg. and 200 mg. daily.

The new compounds, in general, aflect the central nervous system by stimulation or depression in milder dosages or by convulsion in larger dosages. The usefulness of these compounds, in many cases, however, lies in the variations in mood which they produce rather than in measurable stimulation or depression, e.g,, some of the compounds may cause dogs to become very amenable to command and people less bothered 'by worries and external annoyances.

The new compounds are prepared by reacting the appropriate piperidinemethanol with formaldehyde in an inert solvent at an elevated temperature, usually under reflux conditions. The oxazolopyridines are derived from Z-piperidinemethanols, the 3-oxa-5-azabicyclo [3.1.3] nonanes from S-piperidinemethanols and the 3-oXa-5- azabicyclo [3.2.2] nonanes from 4-piperidinemetl1anols.

The piperidinemethanols used as reactants in the preparation of the compounds of this invention are described in United States Patent 2,624,739; in our copending application Ser. No. 462,122, filed October 13, 1954, now abandoned; in application Serial No. 417,956, filed March 22, 1954, now abandoned, of Schumann et al., now abandoned; and in copending application Serial No. 487,- 464,- filed February 10, 1955, now abandoned, of Tilford et al. These piperidinemethanols can be represented by the generic formula in which S, n, R, R", and R have the same significance as above and the radical methanols while Methods G and H produce the corresponding piperidinemethanols directly.

R is used to represent radicals R and R which in these instances are identical.

Examples 1 to 11 below illustrate the preparation of representative intermediate piperidinemethanols which can be converted to the compounds of this invention by reaction with formaldehyde according to the procedures described in Examples 12 to 27. It is to be understood, however, that these specific examples are for illustration only and are not to be construed as limiting the scope of the invention.

EXAMPLE 1 Alpha-pheHyI-aZpha-benZyI-Z-piperidinemethanol HCl Method A was used to prepare alpha-phenyl-alp-ha- 'benzyl-2-pyridinemethanol as follows:

To the Grignard reagent prepared from 126 g. (1 mole) of benzyl chloride, 29 g. (1.2 mole) of magnesium turnings and 500 ml. of dry ether was added 166 g. (0.9 mole) of 2-benzoylpyridine in 150 ml. of dry ether at about 20 C. over a period of 30 minutes with stirring. The mixture was allowed to Warm up to 25-30 C. and decomposed with ammonium chloride solution. The mixture was filtered and the precipitate was washed with water; yield: 160 g. (58%); M.P. 100-101 C. The ether layer from the filtrate was evaporated to one-half volume and diluted With 2 volumes .of 70-90 petroleum ether, cooled and filtered; yield: 53 g. (19%) of additional product melting at 101-102 C. An analytical sample melted at 104- 105 C.

Analysis.--Calcd. for C H ON: C, 82.89%; H, 6.23%. Found: C, 82.78%; H, 6.50%.

The hydrochloride, prepared by dissolving the above base in 2-propanol followed by treatment with alcoholic hydrogen chloride, cooling and filtering, melted at 188-190 C. (decomposition).

Analysis.-Calcd. for C H ON-HCl: C, 73.21%; H, 5.82%. Found: C, 72.85%; H, 5.93%.

A mixture of 41 g. (0.15 mole) of the above base in 275 ml. of methanol was treated with 10-12 ml. of concentrated hydrochloric acid at C.; 0.7 g. of platinum oxide catalyst was added and the mixture was shaken in the presence of hydrogen (initial pressure of 60 lbs.) until the theoretical amount of hydrogen was absorbed. The mixture was filtered and the filtrate was evaporated to a volume of about 100 ml. and 300 ml. of hot ethyl acetate was added. The mixture was cooled and filtered; yield: 33 g. (79%); M.P. 235-236 C. (decomposition).

Analysis..Calcd. for C H ON-HCl: C, 71.79%; H, 7.61%. Found: C, 71.44%; H, 7.77%.

The filtrate was concentrated and second and third crops were obtained; the second crop (2.0 g.) melted at 230-234 C. (decomposition); the third crop melting at 269270 C. was recrystallized twice to yield 2 g. of a second racemate melting at 288289 C. (decomposition) in 4% yield.

Analysis.-Calcd. for C H ON-HCl: C, 71.79%; H, 7.61%. Found: C, 72.08%; H, 7.75%.

EXAMPLE 2 Alpha, alpha-di- (.Z-thienyI) -2-piperz'dinemethanobHCl To. 14.5 g. (0.6 mole) of magnesium turnings in 250 ml. of dry ether was added over a period of an hour volume.

98 g. (0.6 mole) of 2-bromothiophene in 100 ml. of dry ether with stirring under reflux (Method G). The thienylmagnesium bromide solution thus prepared was cooled to 20 C. during 20-30 minutes addition of 18 g. (0.115 mole) of ethyl pipecolin'ate in 50 ml. of dry ether. The mixture was allowed to warm up to 25-30 C. and decomposed with aqueous ammonium chloride solution. The ether solution was separated and concentrated on the steam bath to approximately /2 The concentrate was diluted with 3 volumes of hot petroleum ether, cooled at -12 C overnight, and filtered; yield: 18 g. (56%); M.P. 124125 C.

Analysis.-Calcd. for C H ONS C, 60.17%; H, 6.14%; S, 22.94%. Found: C, 60.39%; H, 6.30%, S, 22.88%.

The base was converted to the hydrochloride; M.P.

240-241 C. (decomposition).

Analysis.-Calcd. C H ONS -HCl: C, 53.24%; H, 5.74%; S, 20.30%. Found: C, 53.16%; H, 5.86%;

EXAMPLE 3 Alpha,alpha-di-(p-phenetyl) -2-piperidinemethan0l'HCl Method D was followed using 50 g. (0.25 mole) of p-bromophenetole, 3.5 g. (0.5 mole) of lithium and 18.2 g. (0.12 mole) of ethyl picolinate. A yield of 8 g.

EXAMPLE 4 Alpha-phenyl-alpha-(p-ethylphenyl)-2-piperidinemethanol HCl Alpha-phenyl-alpha (p ethylphenyl) 2 pyridinemethanol was prepared by Method B (from Z-benzoyl pyridine and a lithium reagent prepared from lithium and. p-bromoethylbenzene) and was obtained in 62% yield: M.P. 59-61 C.

Analysis.-Calcd. for C H ON-HCI: C, 73.72%; H, 6.62%. Found: C, 82.87%; H, 6.58%.

The hydrochloride had a M.P of 156-157 C. (decomposition) Analysis.Calcd. for C H ON-HCl: C, 73.72%; H, 6.19%. Found: C, 73.89%; H, 5.90%.

The pyridine hydrochloride was hydrogenated to give the product which was obtained in two forms: (1) 47% yield: M.P. 323-324" C. (decomposition) and (2) 20% yield; M.P. 271-273 C. (decomposition).

Analysis.-Calcd. for C H ON'HCl: C, 72.40%; H, 7.90%. Found: (1) C, 71.74%; H, 7.91%; (2) C, 71.70%; H, 7.69%.

8 EXAMPLE 5 Alpha-phenyl-alpha-(p-fluorophenyl)-2-piperidi1te methanol -HCl Alpha-phenyl-alpha (p fluorophenyl) 2 pyridin methanol was prepared by Method C (frompyridyllithium and p-fluorobenzophenone) and was obtained in 40% yield: M.P. 8385 C.

Analysis.-Calcd. for C H ONF: C, 77.40%; H, 5.05%. Found: C, 77.39%; H, 5.10%.

The hydrochloride melted at 187189 C. (decomposition). I

Analysis.-Calcd. forC H ONF-HCl: C, 68.45%; H, 4.79%. Found: C, 68.52%; H, 4.84%.

The hydrochloride was hydrogenated to the corresponding piperidinemethanol'fiCl which was obtained in 67% yield: M.P. 288289 C. (decomposition).

Analysis.Calcd. for C H ONF-HCl: C, 67.17%; H, 6.26%. Found: C, 67.21%; H, 6.45%.

EXAMPLE 6 Alpha-phenyl-alpha-(m-chlorophenyl)-2-piperidinemethanol HCl EXAMPLE 7 Alpha-phenyl-alpha- (o-chlorophenyl) -2-piperid inemethanol HCl Method C was used to prepare alpha-phenyl-alpha-(ochlorophenyl)-2-pyridinemethanol-HC1 (from o-chlorobenzophenone and pyridyl lithium) which was obtained in 51% yield: M.P. 260262 C. The corresponding piperidinemethanol was obtained by hydrogenation: yield 79%; M.P. 266268 C. (decomposition).

Analysis.Calcd. for C H ONCl-HCl: C, 63.90%; H, 6.26%. Found: C, 63.81%; H, 6.12%.

EXAMPLE 8 A lph'a-phenyl-alpha- (p-bromophenyl -2-piperidinemethanol -HC1 Method C was used to prepare alpha-phenyl-alpha-(pbromophenyl)-2-pyridinemethanol (from p-bromobenzophenone and a lithium reagent prepared from n-butyllithium and 2-bromopyridine) and was obtained in 68% yield: M.P. 96 C.

Analysis.-Ca1cd. for C I-I ONBr: C, 63.53%; H, 4.15%. Found: C, 63,52%; H, 4.23%.

The hydrochloride melted at 203204 C. (decomposition).

Analysis.Calcd. for C H ONBr-HCI: C, 57.39%; H, 4.01%. Found: C, 57.26%; H, 4.09%.

The hydrochloride was hydrogenated to the corresponding piperidinemethanol-HCl which was obtained in two forms: (1) yield 20%; M.P. 314315 C. (decomposition) and (2) yield 22%; M.P. 275276 C. (decomposition).

Analysis.Calcd. for C H ONBr-HCl: C, 56.48%; H, 5.53%. Found: (1) C, 56.38%; H, 5.59%; (2) C, 56.37%; H, 5.75%.

6. EXAMPLE 9 Alpha,alpha-di-(oJolyl) fZ-piperidinemethanol-HC1 Method D was followed using ethyl picolinate and a lithium reagent prepared from o-bromotoluene and lithium. A yield of 74% of crystals melting at 119-120" C C. was obtained and was alpha,alpha-di-(o-tolyl) -2-pyridinemethanol.

Analysis.Calcd. for C H ON: C, 83.01%; H, 6.62%. Found: C, 83.08%; H, 6.87%.

The hydrochloride was prepared by the procedure of Example 1, M.P. 193194 C.

Analysis.-Calcd. for C H ONCl: C, 73.72%; H, 6.19%. Found: C, 73.58%; H, 6.18%.

Hydrogenation of the hydrochloride gave the desired alpha,alpha-dio-tolyl) -2-piperidinemethanol HCl. M.P. 255-256" 0., yield 92%. V

Analysis.Calcd. for C H ONCl: C, 72.40%; H, 7.90%. Found: C, 72.28%; H, 7.86%.

' EXAMPLE 10 A lpha-phenyflalpha- (m-tolyl) -2-piperidinemethan0l Method B was followed using 2-benzoylpyridine and a lithium reagent prepared from lithium and m-bromotoluene. A yield of 86% of crystals melting at 90-91 C. was obtained and was alpha-phenyl-alpha-(m-tolyl) -2- pyridinemethanol.

Analysis.Calcd. for C H ON: C, 82.89%; H, 6.23%. Found: C, 82.90%; H, 6.42%.

Hydrogenation gave the desired alpha-phenyl-alpha- (m-tolyl) -2-piperidinemethanol.

EXAMPLE 11 Alpha,alpha-di-(p-tolyl) -4-methyl-2-piperidinemezhanol I-ICl Alpha,alpha di-(p-tolyl)-4-methyl-2-pyridinemethanol was prepared by the condensation of gamma-picoline with di-p-tolylketone in the presence of aluminum, mercuric chloride and iodine, M.P. 107-109 C., yieldv EXAMPLE 12 1,1 -di-(2-thienyl -h eptahydrooxazolo-[A-a] pyridine'Hcl A mixture of 6 g. (0.019 mole) of alpha,alpha-di-(Z- thienyl)-2-piperidinemethanol-HCl, prepared in Example 2 above, 4 ml. (0.05 mole) of formalin and ml. of methanol was refluxed for 16 hours and then evapor ated on a steam bath. The residue was dissolved in ml. of ethyl acetate, cooled and filtered; yield: 5 g.

(80%); M.P. 208-210 C. (decomposition). An analytical sample melted at 210 212" C. (decomposition).

Analysis.-Calcd. for C H ONS -HCl: C, 54.94%; H, 5.53%; S, 19.46%. Found: C, 54.81%; H, 5.61%; S, 19.65%.

This compound exhibits activity as a depressant fo the central nervous system. 77 l 7 EXAMPLE 13 J ,1 -di-(o-tlyl)-heptahydrooxazolo-[3,441] pyridine-HCl The procedure of Example 12 was carried out using g. (0.03 mole) of alpha,alpha-di-(o-tolyl)-2-piperi- 'dinemethanol-HCl, prepared in Example 9 'above, 8 ml.

EXAMPLE '14 1,1 -diph eny l-h ep tahydrooxazolo- [3,4-a] pyridine maleate A mixture of 3 .g. (0.011 mole) of alpha,alpha-diphenyl-2-piperidinemethanol (Example 1 of US. 2,264, 739), 1.8 g. (0.22 mole) of formalin and 50 ml. of methanol was refluxed for 16 hours. The reaction mixture was evaporated to one-half volume on a steam bath, cooled, and filtered; yield: 2.8 g. (92%); M.P. 117-121 C.

Analysis.Calcd. for C H ON: C, 81.69%; H, 7.58%. Found: C, 82.41%; H, 8.19%.

The acid maleate salt was obtained by cooling a solution of 2.8 g. (0.01 mole) of the above base and 1.2 g. (0.01 mole) of maleic acid in methanol-ether; yield: 2 g. (50%); M.P. 158-'159 C.

Analysis-Calcd. for C H ON-C4H O :C, 69.86%; H, 6.38%. Found: C, 69.88%; H, 6.73%.

This compound exhibits activity as a stimulant for the central nervous system.

EXAMPLE 1-phenyl-1-(m-t0lyl) -heptahydr00xaz0l0- [3,4-a pyridine maleate The procedure of Example 14 was carried out using alpha phenyl alpha (m tolyl) 2 -piperidinemethanol, prepared in Example 10 above, as the primary reactant. The desired product, obtained as above, had a M.P. of 134-136 C. (decomposition).

Analysis:-Calcd. for C H ON'C H O C, 70.40%; H, 6.65%. Found: C, 70.55%; H, 6.61%.

This compound exhibits activity as a stimulant for the central nervous system.

EXAMPLE 16 1 -phenyl-1 -benzyl-heptahydrooxazolo- [3,4-a] pyridine maleate The procedure of Example 14 was carried out using alpha phenyl alpha benzyl 2 -pipcridinemethanol, prepared in Example 7, as the primary reactant. The desired product, obtained as above had a M.P. of 114116 C. (hygroscopic; decomposition).

Analysis-Caktd. for CZQHZ3ON'C4H4O4C C, H, 6.65%. Found: C, 70.21%; H, 6.74%.

This compound exhibits activity as a stimulant for the central nervous system.

EXAMPLE 17 I -phenyl-1 (m-chlorophenyl) heptahydrooxazolo- [3,4-a]pyridine maleate The procedure of Example 14 was carried out using alpha phenyl alpha (m chlorophenyl) 2 piperidinemethanol, prepared in Example 6, as the primary reaotant. The free base was isolated as above; M.P. 83-85 C.

A'naly'sis.Ca1cd. for C H ONCI: C, 72.73%; H, 6.43%. Found: C, 72.92%; H,'6.47%.

The acid maleate salt was obtained as in Example 14; M.P. 126-128 C. (decomposition).

Analysis. Calcd. for C H dONCl-C H O r C, 64.26%; H, 5.63%. Found: C, 64.21%; H, 5.75%.

This compound exhibits activity as a stimulant for the central nervous system.

-EXAMPLE 1 8 1,1-di-(p-chlor0phenyl) -heptahydr00xaz0l0 [3,4-al pyridine maleate The procedure of Example 14 was carried out using alpha-alpha di (p chlorophenyl) 2 -piperidinemethanol (Compound No. 13(c) of Table I of Serial No. 462,122) as the primary reactant. The free base was isolated as'above; M.P. 169-171" C.

Analysis.Calcd. for C H ONCI C, 65.52%; H, 5.50%. Found: C,-65.32%; H, 5.82%.

The acid maleate salt was-obtained as in Example 14; M.P. 132-134 C. (decomposition).

Analysis.CalCd. C9H19ONC12C4H404I C, H, 4.99%. Found: C, 59.38%; H, 5.18%.

This'compound exhibits activity as a stimulant for the central nervous system.

EXAMPLE 19 S p iro (anthracene-9 [1 0H] ,1 I-heptahydrooxazolw [3 ,4-a-l pyridine) maleate The intermediate, 9-(2-piperidyl)-9-anthrol (Compound 31(c) of Table I of Sen'al No. 462,122), was converted to the desired product by the procedure of Example 14. The free basemelted at 162-l64 C.

Analysis.Calcd. for C H ON: C, 82.44%; H, 7.27%. Found: C, 82.29%; H, 7.37%.

The acid maleate melted at 168-169" C. (decomposition).

Analysis.Calcd. for C H ON-C H O C, 70.75%; H, 6.18%. Found: C, 70.62%; H, 6.23%.

This compound exhibits activity as a depressant for the central nervous system.

EXAMPLE 20 1,1 -di- (p-tolyl -1 -methy l-heptahydrooxazolo- [3,4-a] pyridine -HCl The intermediate, alpha,alpha-di-(p-tolyl)-4-methyl-2- piperidinemethanol-HCl prepared in Example 11 above, was converted to the desired product by the procedure of Example 12: the hydrochloride melted at 295 C. (decomposition) Analysis.-Calcd. for C H ON-HCl: C, 73.81%; H, 7.88%. Found: C, 73.97%; H, 8.40%.

EXAMPLE 21 Z-p-ch lorophenyl-Z-pheny l-3-0xa-5-zzzabicycl0 [3 .2.2] nonane maleate Z-benzyl-Z-phenyl-3-oxa-5-azabicyclo[3.2.2]nonane maleate A mixture of 14.3 g. (0.045 mole) of the intermediate alpha benzyl alpha phenyl 4 piperidinerncthanol' HCl "(Compound No. 3(0) of Table II of SN. 462,122

and Example II of S.N. 487,464), 14 ml. of formalin, 3.7

g. of sodium bicarbonate, and 250 ml. of methanol was refluxed for 16-24 hours. The reaction mixture was diluted with two volumes of water, made alkaline with 2.5 g. of potassium hydroxide, cooled, and filtered. The crude free base was recrystallized from 80% methanol; yield: 11 g. (83%); M.P. 144146 C.

Analysis.-Ca1cd. for C H ON: C, 81.86%; H, 7.90%. Found: C, 81.40%; H, 8.37%.

The above desired free base (5.5 g.; 0.0178 mole) was dissolved in 50 ml. of benzene and a solution of 2 g. (0.0178 mole) of maleic acid in 50 ml. of 1:1 benzenemethanol was added. The mixture was cooled and filtered; yield: 4 g. as first crop; M.P. 168-170 C. dec. Recrystallization from methanol-benzene gave the pure desired acid maleate salt melting at 172174 C. dec.

Analysis.Calcd. for C H ON-C H O C, 70.40%; H, 6.65%. Found: C, 70.42%; H, 6.90%.

This compound exhibits activity as 'a. depressant for the central nervous system.

EXAMPLE 23 2-(0-t0lyl -2-phenyl-3-0xa-5 -azabicycl[3 .2 .2lnonane maleate The intermediate alpha (o tolyl) alpha-phenyl 4- pyridimethanol-HCl was prepared by Method B (from 4-benzoyl pyridine and a lithium reagent prepared from lithium and o-bromotoluene); yield: 75%; M.P. 214- 215 C. dec.

Analysis.Calcd. for C H ON'HCl: C, 73.19%; H, 5.82%. Found: C, 72.96%; H, 5.86%.

It was hydrogenated to the next intermediate, alpha- (o-tolyl)-alpl1a-phenyl-4-piperidinemethanol-HC1 by the procedure of the second part of Example 1; M.P. 256- 257" C. dec.

Analysis.-Calcd. for C H ON-HCl: C, 71.79%; H, 7.61%. Found: C. 71.43%; H, 7.47%.

The desired bicyclononane maleate salt was obtained by the procedure of Example 22; M.P. 174-175 C. dec.

Analysis.-Calcd. for C H ON-C H O C, 70.40%; H, 6.65%. Found: C, 70.25%; H, 6.55%.

This compound exhibits activity as a depressant for the central nervous system.

EXAMPLE 24 2,2-di- (o-tolyl) -3-0xa-5-azabicycl0 [3 .2.2 nonane maleate The intermediate alpha,a1ph.a-di-(o-tolyl)-4-pyridinemethanol-HCl obtained by Method D (from ethyl isonicotinate and o-lithiotoluene) melted at 208 210 C. dec.

Analysis.-Calcd. for c, H,,oN-Hc1= C, 73.72%; H, 6.19%. Found: C, 73.72%; H, 6.26%.

It was hydrogenated by the procedure of Example 1 to the next intermediate, alpha,alpha-di-(o-tolyl)-4-piperidinemethanol-HCI; M.P. 305-306 C. dec.

Analysis.-Calcd. for C H ON-HCl: C, 72.40%; H, 7.90%. Found: C, 72.27%; H, 8.02%.

'The desired bicyclononane acid maleate salt was obtained by the procedure in Example 22; M.P. 190-191 C. dec.

Analysis.Calcd. for C H ON-C H O C, 70.91%; H, 6.90%. Found: C, 70.68%; H, 7.27%.

This compound exhibits activity as a depressant for the central nervous system.

EXAMPLE 25 2-(0-methylbenzyl) -2-phenyl-3-oxa-5-azabicyclo [3 .2.2] nonane maleate The intermediate alpha (o methylbenzyl) alphaphenyl-4-pyridinemethanol-HCl was obtained using Method A (from 4-benzoyl pyridine and a reagent preared from magnesium and o-methyl-benzylchloride); M.P. 234236 C..dec.

10 Analysis.Ca1cd. for c,,H,,oN-Hc1= c, 73.72%; a, 6.19%. Found: C, 73.42%; H, 6.25%.

The next intermediate, alpha-(o-methylbenzyl) -alphaphenyl-4-piperidinemethanol-HCl was obtained by the hydrogenation procedure of Example 1; M.P. 245-246 C. dec.

Analysis.Calcd. for C H ON-HCI: C, 72.40%; H, 7.90%. Found: C, 72.39%; H, 7.80%.

The desired bicyclononane acid maleate salt was obtained by the procedure of Example 22; M.P. 197198 C. dec.

Analysis.Calcd. for C H ON-C H O C, 70.91%; H, 6.90%. Found: C. 71.09%; H, 7.09%.

This compound exhibits activity as a depressant for the central nervous system.

EXAMPLE 26 2-(0-t0lyl -2-benzyl-3-oxa-5 -azabicycl0[3 .2 .2] nonane maleate The intermediate alpha (o tolyl) a1pha-benzyl-4- pyridinemethanol-HCI was obtained by the procedure of Method A using 4-(o-tolyl)pyridyl ketone (from 4-cyanopyridine and o-tolyllithium); new compound M.P. 40-41 C.

Analysis.Calcd. for C H ON: C, 79.18%; H, 5.62%; N, 7.10%. Found: C, 79.20%; H, 5.62%; N, 7.25%.

M.P. 244246 C. dec.

Analysis.Calcd. for C H ON-HCl: C, 73.72%; H, 6.19%. Found: C, 74.10%; H, 6.23%.

The next intermediate, alpha(o-tolyl)-alpha-benzy1-4- piperidinemethanol-HCl was obtained by the hydrogenation procedure of Example 1; M.P. 255257 C.

Analysis.-Calcd. for C H ON-HCl: C, 72.40%; H, 7.90%. Found: C. 72.51%; H, 8.03%.

The desired bicyclononane acid maleate salt was prepared by the procedure of Example 22; M.P. 167- 169 C.

Analysis.-Calcd. for C H ON-C,H O C, 70.91%; H, 6.90%. Found: C, 70.95%; H, 7.13%.

This compound exhibits activity as a depressant for the central nervous system.

EXAMPLE 27 2,2-diphenyl-3-0xa-5-azabicycl0[3.1.31-n0nane maleate 1,1-di-(o methoxyphenyl) heptahydrooxazo1o[3,4-al

pyridine 1,1, di (p isopropoxyphenyl) heptahydrooxazolo [3,4-a1pyridine 1,1-di (o [n butoxy] phenyl) heptahydrooxazolo 3 ,4-a] pyridine 1,1 di- (m-methoxyphenyl)-heptahydrooxazolo[3,4-a]

pyridine l-phenyl 1 methoxyphenyl-heptahydrooxazolo[3,4-a]

pyridine 1 (o tolyl) 1 (o-ethoxyphenyl) heptahydrooxazolo [3,4-a1pyridine 1,1 di (p-isopropylphenyl)-heptahydrooxazolo[3,4-a]

pyridine 1,1 .di (p -isobutylphenyl)-heptahydrooxazolo[3,4-a]

pyridine 1,1 di (o ethylphenyl) heptahydroxazolo[3,4-a]

pyridine 1 phenyl 1 (o-[n-propyllphenyl)-heptahydrooxazolo [3,4-a1pyridine 1,1-dibcnzyl-heptahydrooxazolo[3,4-alpyridine 1 phenyl 1 (p fluorophenyl) heptahydrooxazolo '[3,4-a]pyridine 1 phenyl l-(o-iodophenyl)heptahydrooxazolo[3,4-a]

pyridine 1,1 di (p bromophenyl) heptahydrooxazolo[3,4-a]

pyridine 1,1 .di (2,4-dichlorophenyl) heptahydrooxazolo[3,4-a]

pyridine 1,1 'di (2,4,6 trichlorophenyl) heptahydrooxazolo [3,4-alpyridine 1,1-di-(p-pl1enetyl) -heptahydrooxazolo 3,4-a] pyridine 1,1 di (2,4 dimethoxyphenyl) heptahydrooxazolo [3,4-alpyridine 1,1 di (2 methoxy 3-ethoxyphenyl) -hepta.hydrooxazolo[3,4-'a]pyridine 1 (0 methoxyphenyl) 1 (p isopropoxyphenyl)- heptahydrooxazoloE 3 ,4-a] pyridine 1,1 di (2,4,6 trimethylphenyl) heptahydrooxazolo [3,4-alpyridine 1,1 di (2 methyl 4 isopropylphenyl) hepta'hydrooxazolo [3,4-a] pyridine 1,1 di- (2-ethyl-4-[t-butylphenyl])-heptahydrooxazolo [3,4a]pyridine Other 3-oxa-5-azabicyclo [3.1.3]nonanes of this invention which are prepared by the procedures of the above examples include:

2,2-diphenyl-7,8-diethyl-3-oxa-5-azabicyclo[3.1.3]nonane 2,2-dibenzyl-6-methyl-3-oxa-5-azabicyclo [3 1 .3 nonane 2,2diphenethyl-8-ethyl-3-oxa-5-azabicyclo[3.1.3]nonane 2-phenyl-2-p-tolyl-3-oxa5-azahicyclo[3.1.3]nonane 2-tolyl-2-m-xylyl-3-oxa-5-azabicyclo[3.1.3]nonane 2,2-di-p-methoxyphenyl-3 -oxa-5-azabicyclo [3 1 .3]

2,2 di p isopropoxyphenyl-3-oxa-5-azabicyclo[3. 1.3]

nonane 2-o-ethoxyphenyl 2 phenyl-3-oxa-5-azabicyc1o[3.13]

nonane 2,2 di-p-chlorophenyl-8-methyl-3 -oxa-5-azabicyclo[ 3 1 .3]

nonane 2,2-di-o-bromophenyl 6-ethyl-3-oXa-5-azabicyclo [3.1.3]

nonane 2,2-di-p-iodophenyl-3 -oxa-5-azabicyclo[3.1.3]nonane 2-(2,4,6-trichlorophenyl) -2-phenyl 3 oxa-S-azabicyclo [3.1.3]nonane Spiro anthracene-9 ,2- 3-oxa 5 azabicyclo [3.1.3]

nonane Other 3-oxa-5-azabicyclo[3.2.2]nonanes of this invention which are prepared by theprocedures of the above examples include:

2,2 diphenyl-7,8-dimethyl 3 'oxa-5-azabicyclo[3.2.2]

nonane 2,2-dibenzyl-8-ethyl-3-oxa-5-azabcyclo[3.2.2]nonane 2-phenyl-2-phenethyl-3-oxa-5 -aza bicyclo 3 .2.2 nonane 2,2-ditolyl-tS-methyl-3-cxa-5-azabicyclo[3.2.2]nonane 2,2 di-o-methoxyphenyl-3-oxa-5-azabicyclo[3.2.2]nonane 2-p-ethoxyphenyl-2-p-isopropoxyphenyl 3 oxa-S-azabicyclo[3.2.2]nonane 2,2-di-o-chlorophenyl-3-oxa-5-azabicyclo[3.2.2 nonane 2,2-di-p-bromophenyl-3-oxa-5-azabicyclo[3.2.2]nonane 2,2-di-p-iodophenyl-3-oxa-5-azabicyclo[3.2.2]nonane 2-p-luorophenyl- 2 :phenyl 3-oxa-5-azabicyclo[3.2.2]

nonane 2-(2,4,6drichlorophen3 )-2-pheny1 3 oxa-S-a'zabicyclo [3.2.2]nonane Spiro[anthracene-9 ('10),2'-(30xa 5 azabicyclo["3.2.2]

nonane) 1 it being understood that in actual .practice, the dosage forms will be prepared in suitable quantities, and the amounts adjusted accordingly.

EXAMPLE 28 25 mg. tablets-Twenty five mg. of the maleate of 2,2-di- (o-tolyl) -3-oxa-5-azabicyclo 3 .2.2] nonane (Example 24), 48 mg. of powdered sugar, and 32 mg. of corn starch are mixed and granulated with 10 per cent gelatin solution. The granulation is dried and ground to fine granules for tableting. About 1 percent'rnagnesium stearate is added as a lubricant, together with suflicient corn starch to give a weight of 2.5 grains per tablet. The product is compressed on a single punch or rotary machine using a inch punch.

EXAMPLE 29 500 mg. tablets. Five hundred mg. of the maleate of 2,2-di-(o-tolyl)-3-oxa-5-azabicyclo[3.2.2]nonane (Example 24) in finely powdered form is admixed with 60 mg. of corn starch and mg. of powdered sugar and .then granulated with IO-percent gelatin solution. Thegranulation is dried and ground to size suitable for tableting. About 1 percent magnesium stearate is added as a lubricant, together with sufiicient corn starch to give a weight of 700 mg. per tablet. The product is compressed on a single punch or rotary machine using a 5 inch punch.

The tablets of Examples 28 and 29 can be suitably coated if desired, as, for example, with sugar.

EXAMPLE 3O 25 mg. capsule.TWenty-five mg. of the maleate of spiro anthracene 9- 10H] 1-heptahydrooxazolo [3 ,4-a] pyridine) (Example 19) is admixed with corn starch in quantity required to provide suflicient bulk for the desired size capsule, and the mixture is encapsulated.

EXAMPLE 31 500 mg. capswle.Five hundred mg. of the maleate of 2,2-di-(o-tolyl)-3-oxa-5-azabicyclo[3.2.2]nonane (Example 24) is admixed with sufiicient corn starch to give the proper bulk for the desired size capsule, and the'mixture is encapsulated.

EXAMPLE 32 Injectable suspension, 100 mg. per mL-The following ingredients are sterilized separately: 100 mg. of the maleate of 2,2-di-(o-tolyl)-3-oxa-5-azabicyclo[3.2.2]nonane (Example 24), 0.1 ml. of Tween '80 and q.s. corn oilto make a final volume of one ml. These ingredients are admixed aseptically. Particle size can [be achieved by use of micronized material or by use of a ball mill, maintaining aseptic conditions. The above suspension can be administered subcutaneously and intramuscularly.

EXAMPLE 33 Liquid (syrup) 25 mg.-per teaspoom-Twenty-five mg. of the hydrochloride of 1,1-di-(2-thienyl)-heptahydrooxazolo[3,4-a] pyridine (Example 12) is dissolved in onenil. of water. Five mg. of sodium benzoate, 3.5 ml. of liquid sugar,-5 mg. of citric acid, and 0.375 of butoben are added and stirred until'dissolved, using gentle heat it necessary. Flavor, as desired, and water q.s. 5 ml. are then added.

13 EXAMPLE 34 Liquid (syrup) 500 mg. per tablespoon-Five hundred EXAMPLE 35 Injectable solution, 100 mg. per ml.-ne hundred mg. of the hydrochloride of 1,1-di-(2-thienyl)-heptahydrooxazolo[3,4-a]pyridine (Example 12) and water for injection q.s. one ml. are mixed and warmed gently till solution is accomplished. The solution is filtered through an O3 porosity Selas filter, using sterilized equipment under aseptic conditions, and is used freshly made up for injection.

The other compounds of Examples 12m 27 can be used to prepare pharmaceutical compositions such as those of Examples 28 to 35.

This application is a continuation-impart of our pending application Serial No. 485,624, filed February 1, 1955, now abandoned.

We claim:

1. The compounds of the formulas selected from the group consisting of RI! R!!! in which s signifies that the rings are saturated, n represents an integer from 1 to 4 inclusive, R represents a substitutent selected from the group consisting of the hydrogen atom and the methyl and ethyl radicals and R" and R' represent substituents selected from the group consisting of the phenyl, phenyl lower alkyl, lower alkylphenyl, lower alkoxyphenyl, halophenyl and thienyl radicals and in which R and 11" when taken together with the carbon atom to which they are attached represent 9 10) -anthranylidene.

2. 1,1-di-(2-thienyl)-heptahydrooxazolo[3,4-alpyridine.

3 1,1-di-(o-tolyl) -heptahydrooxazolo 3,4-a] pyridine.

4. 1,1-diphenyl-heptahydrooxazolo[3,4-a1pyridine.

5. Spiro anthracene-9(10H),1'-heptahydrooxazolo[3,4- alpyridine.

6. 2,2-di- (o-tolyl)-3-oxa-5-azabicyc1o[3.2.2]nonane.

References Cited in the file of this patent Berichte der Deut. Chem. Gesell. (1921), vol. 54B, pp. 3012, 3019, 3020. 

1. THE COMPOUNDS OF THE FORMULAS SELECTED FROM THE GROUP CONSISTING OF 